Marine Drugs

Editorial

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3 pages, 200 KiB

Open AccessEditorial

Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances

by Emiliano Manzo

Mar. Drugs 2021, 19(4), 208; https://doi.org/10.3390/md19040208 - 8 Apr 2021

Cited by 6 | Viewed by 2381

Abstract

The sea covers more than 70% of Earth’s surface and contains more than 300,000 organisms with huge biodiversity [...] Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

Research

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9 pages, 1643 KiB

Open AccessArticle

Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars

by Anna Esposito, Daniele D’Alonzo, Stefano D’Errico, Eliana De Gregorio and Annalisa Guaragna

Mar. Drugs 2020, 18(11), 572; https://doi.org/10.3390/md18110572 - 19 Nov 2020

Cited by 8 | Viewed by 2374

Abstract

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a–b and 11a–b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol [...] Read more.

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a–b and 11a–b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I₂/ImH activating system, which provided the desired compounds in high yields (94–96%) by a one-pot procedure. The substantial increase in the lipophilicity of 10a–b and 11a–b is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties. However, assays are currently hampered by solubility problems; therefore, alternative administration strategies will need to be devised. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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18 pages, 5450 KiB

Open AccessArticle

Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

by Sarah Mazzotta, Gabriele Carullo, Aniello Schiano Moriello, Pietro Amodeo, Vincenzo Di Marzo, Margarita Vega-Holm, Rosa Maria Vitale, Francesca Aiello, Antonella Brizzi and Luciano De Petrocellis

Mar. Drugs 2020, 18(10), 519; https://doi.org/10.3390/md18100519 - 18 Oct 2020

Cited by 13 | Viewed by 4007

Abstract

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient [...] Read more.

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC₅₀ of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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8 pages, 975 KiB

Open AccessArticle

A Concise Route for the Synthesis of Tetracyclic Meroterpenoids: (±)-Aureol Preparation and Mechanistic Interpretation

by Antonio Rosales Martínez, Lourdes Enríquez, Martín Jaraíz, Laura Pozo Morales, Ignacio Rodríguez-García and Emilio Díaz Ojeda

Mar. Drugs 2020, 18(9), 441; https://doi.org/10.3390/md18090441 - 26 Aug 2020

Cited by 9 | Viewed by 2569

Abstract

A new concise general methodology for the synthesis of different tetracyclic meroterpenoids is reported: (±)-aureol (1), the key intermediate of this general route. The synthesis of (±)-aureol (1) was achieved in seven steps (28% overall yield) from (±)-albicanol. The [...] Read more.

A new concise general methodology for the synthesis of different tetracyclic meroterpenoids is reported: (±)-aureol (1), the key intermediate of this general route. The synthesis of (±)-aureol (1) was achieved in seven steps (28% overall yield) from (±)-albicanol. The key steps of this route include a C–C bond-forming reaction between (±)-albicanal and a lithiated arene unit and a rearrangement involving 1,2-hydride and 1,2-methyl shifts promoted by BF₃•Et₂O as activator and water as initiator. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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11 pages, 1470 KiB

Open AccessCommunication

First Total Synthesis of 5′-O-α-d-Glucopyranosyl Tubercidin

by Wenliang Ouyang, Haiyang Huang, Ruchun Yang, Haixin Ding and Qiang Xiao

Mar. Drugs 2020, 18(8), 398; https://doi.org/10.3390/md18080398 - 29 Jul 2020

Cited by 3 | Viewed by 2631

Abstract

The first total synthesis of 5′-O-α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield [...] Read more.

The first total synthesis of 5′-O-α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribose. The key step involves stereoselective α-O-glycosylation of the corresponding 7-bromo-6-chloro-2′,3′-O-isopropylidene-β-d-tubercidin with 2,3,4,6-tetra-O-benzyl-glucopyranosyl trichloroacetimidate. All spectra are in accordance with the reported data for natural 5′-O-α-d-glucopyranosyl tubercidin. Meanwhile, 5′-O-β-d-glucopyranosyl tubercidin was also prepared using the same strategy. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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12 pages, 1114 KiB

Open AccessArticle

Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole

by Bingbing Zhang, Zhu-Wei Ruan, Dongdong Luo, Yueyue Zhu, Tingbo Ding, Qiang Sui and Xinsheng Lei

Mar. Drugs 2020, 18(7), 344; https://doi.org/10.3390/md18070344 - 30 Jun 2020

Cited by 5 | Viewed by 2346

Abstract

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole’s macrocyclic moiety with S-Me l-Cysteine or Glycine residue [...] Read more.

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole’s macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five–nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol. A molecular modeling study provided rational explanation and structural evidence for the enhanced inhibitory activity. This new finding will aid the design of novel potent HDAC inhibitors. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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16 pages, 2792 KiB

Open AccessArticle

Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

by Wagdy M. Eldehna, Ghada S. Hassan, Sara T. Al-Rashood, Hamad M. Alkahtani, Abdulrahman A. Almehizia and Ghada H. Al-Ansary

Mar. Drugs 2020, 18(4), 190; https://doi.org/10.3390/md18040190 - 2 Apr 2020

Cited by 16 | Viewed by 3421

Abstract

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic [...] Read more.

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic spacer in the natural leads by a more flexible hydrazide linker while sparing the two peripheral indole rings. All the synthesized bis-indoles were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. The most potent congeners 7e and 9a against MCF-7 cells (IC₅₀ = 0.44 ± 0.01 and 1.28 ± 0.04 μM, respectively) induced apoptosis in MCF-7 cells (23.7-, and 16.8-fold increase in the total apoptosis percentage) as evident by the externalization of plasma membrane phosphatidylserine detected by Annexin V-FITC/PI assay. This evidence was supported by the Bax/Bcl-2 ratio augmentation (18.65- and 11.1-fold compared to control) with a concomitant increase in the level of caspase-3 (11.7- and 9.5-fold) and p53 (15.4- and 11.75-fold). Both compounds arrested the cell cycle mainly in the G2/M phase. Furthermore, 7e and 9a displayed good selectivity toward tumor cells (S.I. = 38.7 and 18.3), upon testing of their cytotoxicity toward non-tumorigenic breast MCF-10A cells. Finally, compounds 7a, 7b, 7d, 7e, and 9a were examined for their plausible CDK2 inhibitory action. The obtained results (% inhibition range: 16%–58%) unveiled incompetence of the target bis-indoles to inhibit CDK2 significantly. Collectively, these results suggested that herein reported bis-indoles are good lead compounds for further optimization and development as potential efficient anti-breast cancer drugs. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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28 pages, 3233 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Four New Ricinoleic Acid-Derived 1-O-alkylglycerols

by René Momha, Victor Kuete, Jean-Marie Pagès, Dieudonné Emmanuel Pegnyemb and Paul Mosset

Mar. Drugs 2020, 18(2), 113; https://doi.org/10.3390/md18020113 - 15 Feb 2020

Cited by 11 | Viewed by 3541

Abstract

A series of novel substituted 1-O-alkylglycerols (AKGs) containing methoxy (8), gem-difluoro (9), azide (10) and hydroxy (11) group at 12 position in the alkyl chain were synthesized from commercially available ricinoleic acid [...] Read more.

A series of novel substituted 1-O-alkylglycerols (AKGs) containing methoxy (8), gem-difluoro (9), azide (10) and hydroxy (11) group at 12 position in the alkyl chain were synthesized from commercially available ricinoleic acid (12). The structures of these new synthesized AKGs were established by NMR experiments as well as from the HRMS and elementary analysis data. The antimicrobial activities of the studied AKGs 8–11 were evaluated, respectively, and all compounds exhibited antimicrobial activity to different extents alone and also when combined with some commonly used antibiotics (gentamicin, tetracycline, ciprofloxacin and ampicillin). AKG 11 was viewed as a lead compound for this series as it exhibited significantly higher antimicrobial activity than compounds 8–10. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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11 pages, 1632 KiB

Open AccessArticle

In Vitro Antiproliferative Evaluation of Synthetic Meroterpenes Inspired by Marine Natural Products

by Concetta Imperatore, Gerardo Della Sala, Marcello Casertano, Paolo Luciano, Anna Aiello, Ilaria Laurenzana, Claudia Piccoli and Marialuisa Menna

Mar. Drugs 2019, 17(12), 684; https://doi.org/10.3390/md17120684 - 5 Dec 2019

Cited by 14 | Viewed by 3203

Abstract

Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of [...] Read more.

Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of the substituent groups in the quinone moiety. Aiming to broaden the knowledge of the underlying mechanism of the antiproliferative effect of these prenylated compounds, herein we report the synthesis of two quinones 4 and 5 and of their corresponding dioxothiazine fused quinones 6 and 7 inspired to the marine natural product aplidinone A (1), a geranylquinone featuring the 1,1-dioxo-1,4-thiazine ring isolated from the ascidian Aplidium conicum. The potential effects on viability and proliferation in three different human cancer cell lines, breast adenocarcinoma (MCF-7), pancreas adenocarcinoma (Bx-PC3) and bone osteosarcoma (MG-63), were investigated. The methoxylated geranylquinone 5 exerted the highest antiproliferative effect exhibiting a comparable toxicity in all three cell lines analyzed. Interestingly, a deeper investigation has highlighted a cytostatic effect of quinone 5 referable to a G0/G1 cell-cycle arrest in BxPC-3 cells after 24 h treatment. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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Review

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19 pages, 2652 KiB

Open AccessReview

(Semi)-Synthetic Fucosylated Chondroitin Sulfate Oligo- and Polysaccharides

by Giulia Vessella, Serena Traboni, Antonio Laezza, Alfonso Iadonisi and Emiliano Bedini

Mar. Drugs 2020, 18(6), 293; https://doi.org/10.3390/md18060293 - 1 Jun 2020

Cited by 12 | Viewed by 4225

Abstract

Fucosylated chondroitin sulfate (fCS) is a glycosaminoglycan (GAG) polysaccharide with a unique structure, displaying a backbone composed of alternating N-acetyl-d-galactosamine (GalNAc) and d-glucuronic acid (GlcA) units on which l-fucose (Fuc) branches are installed. fCS shows several potential biomedical [...] Read more.

Fucosylated chondroitin sulfate (fCS) is a glycosaminoglycan (GAG) polysaccharide with a unique structure, displaying a backbone composed of alternating N-acetyl-d-galactosamine (GalNAc) and d-glucuronic acid (GlcA) units on which l-fucose (Fuc) branches are installed. fCS shows several potential biomedical applications, with the anticoagulant activity standing as the most promising and widely investigated one. Natural fCS polysaccharides extracted from marine organisms (Echinoidea, Holothuroidea) present some advantages over a largely employed antithrombotic drug such as heparin, but some adverse effects as well as a frequently found structural heterogeneity hamper its development as a new drug. To circumvent these drawbacks, several efforts have been made in the last decade to obtain synthetic and semi-synthetic fCS oligosaccharides and low molecular weight polysaccharides. In this Review we have for the first time collected these reports together, dividing them in two topics: (i) total syntheses of fCS oligosaccharides and (ii) semi-synthetic approaches to fCS oligosaccharides and low molecular weight polysaccharides as well as glycoclusters displaying multiple copies of fCS species. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances)

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